Fatty acid-antipsychotic compositions and uses thereof

ABSTRACT

The invention provides compositions that include conjugates of a fatty acid molecule, preferably cis-docosahexaenoic acid, and antipsychotic agents. The conjugates are usefull in treating psychotic conditions such as schizophrenia.

RELATED APPLICATION

This application claims priority under 35 U.S.C. §120 from U.S. patentapplication Ser. Nos. 08/651,428, and 08/651,312, both filed May 22,1996 the entire disclosures of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Psychotic conditions such as schizophrenia and related disorders (e.g.schizoaffective disorder), are complex and heterogeneous diseases ofuncertain etiology that afflict approximately 1 to 2% of all populationsworldwide. Schizophrenia is characterized as having both "positivesymptoms" (hallucinations, delusions, and conceptual disorganization)and "negative symptoms" (apathy, social withdrawal, affect, and povertyof speech). Abnormal activity of the neurotransmitter dopamine is ahallmark of schizophrenia. Dopaminergic activity is reduced in themesocortical system (resulting in negative symptoms) and is enhanced inthe mesolimbic system (resulting in positive or psychotic symptoms).Several other neurotransmitters are involved, including serotonin,glutamate, and GABA.

For many years, schizophrenia was treated with classical antipsychoticdrugs, the neuroleptics, that block central dopamine receptors. Theneuroleptics are effective for treating the positive symptoms ofschizophrenia, but have little or no effect on the negative symptoms.The ability of these drugs to antagonize dopamine receptors correlateswith antipsychotic efficacy. Neuroleptic drugs include phenothiazinesincluding aliphatics (e.g., chlorpromazine), piperidines (e.g.,thioridazine), and piperazines (e.g., fluphenazine); butyrophenones(e.g., haloperidol); thioxanthenes (e.g., flupenthixol); oxoindoles(e.g., molindone); dibenzoxazepines (e.g., loxapine) anddiphenylpiperidines (e.g., pimozide).

Unfortunately, neuroleptics-resistant negative symptoms account for mostof the social and vocational disability caused by schizophrenia.Further, neuroleptics cause extrapyramidal symptoms, including rigidity,tremor, bradykinesia (slow movement), and bradyphrenia (slow thought),as well as tardive dyskinesias and dystonias.

The atypical antipsychotics are a different class of antipsychotic drugswhich have a different receptor binding profile and effectivenessagainst the symptoms of schizophrenia. Atypical antipsychotics bindcentral serotonin2 (5-HT2) receptors in addition to D2 dopaminereceptors. Unlike the neuroleptics, they improve negative as well aspositive symptoms. They cause minimal extrapyramidal symptoms and rarelycause tardive dyskinesias, akathisia, or acute dystonic reactions.

The first atypical antipsychotic drug approved for the treatment ofschizophrenia was clozapine. Clozapine binds D2 dopamine receptorweakly, but has a strong affinity for the 5-HT2A receptor. Clozapinealso antagonizes adrenergic, cholinergic, and histaminergic receptors.Clozapine is effective for the treatment of schizophrenia, especiallyfor subjects who do not respond to traditional neuroleptic therapy.Clozapine has been found to be superior to neuroleptics for improvingpsychotic symptoms, and generally is better tolerated.

The side effects of clozapine, however, present problems for safety andpatient compliance. The side effects include sedation, orthostatichypotension, hypersalivation, lowered seizure threshold and, inparticular, agranulocytosis. The incidence of agranulocytosis inpatients taking clozapine is about 1-2%. Agranulocytosis is a seriouscondition characterized by a precipitous drop in the white blood cellcount; the seriousness of the condition mandates that white blood cellcounts be measured each week for patients taking clozapine. Anotherpatient compliance issue is the relatively short half life of clozapinein vivo, which necessitates multiple doses each day to maintaintherapeutic effectiveness.

Fatty acids previously have been conjugated with drugs to help the drugsas conjugates cross the blood brain barrier. For example, DHA(docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranchedfatty acid that previously has been shown to be unusually effective incrossing the blood brain barrier. When DHA is conjugated to a drug, theentire drug-DHA conjugate is transported across the blood brain barrierand into the brain. DHA is attached via the acid group to hydrophilicdrugs and renders these drugs more hydrophobic (lipophilic). DHA is animportant constituent of the brain and recently has been approved as anadditive to infant formula. It is present in the milk of lactatingwomen. The mechanism of action by which DHA helps drugs conjugated to itcross the blood brain barrier is unknown.

Another example of the conjugation of fatty acids to a drug is theattachment of pipotiazine, an antipsychotic, to stearic acid, palniticacid, enanthic acid, undecylenic acid or 2,2-dimethyl-palmitic acid.Pipotiazine is a drug that acts within the central nervous system. Thepurpose of conjugating pipotiazine to the fatty acids was to create anoily solution of the drug as a liquid implant for slow release of thedrug when injected intramuscularly. The release of the drug appeared todepend on the particular fatty acid selected, and the drug was testedfor its activity in the central nervous system.

Lipidic molecules, including the fatty acids, also have been conjugatedwith drugs to render the conjugates more lipophilic than the drug. Ingeneral, increased lipophilicity has been suggested as a mechanism forenhancing intestinal uptake of drugs into the lymphatic system, therebyenhancing the entry of the conjugate into the brain and also therebyavoiding first-pass metabolism of the conjugate in the liver. The typeof lipidic molecules employed have included phospholipids, non-naturallyoccurring branched and unbranched fatty acids, and naturally occurringbranched and unbranched fatty acids ranging from as few as 4 carbonatoms to more than 30 carbon atoms. In one instance, enhanced receptorbinding activity was observed (for an adenosine receptor agonist), andit was postulated that the pendant lipid molecule interacted with thephospholipid membrane to act as a distal anchor for the receptor ligandin the membrane microenvironment of the receptor. This increase inpotency, however, was not observed when the same lipid derivatives ofadenosine receptor antagonists were used, and generalizations thus werenot made possible by those studies.

SUMMARY OF THE INVENTION

It has now been discovered that covalent conjugates of a fatty acid withclozapine have the unexpected property of extended therapeuticeffectiveness. This unexpected property of the conjugate permitsadministration of lower doses of drug (as part of the covalentconjugate) to yield an antipsychotic therapeutic effect, therebyreducing the chances of serious side effects such as agranulocytosis.The unexpected property of the conjugate also permits less frequentdosing to maintain an antipsychotic therapeutic effect relative tounconjugated clozapine.

According to one aspect of the invention, a composition of matter isprovided. The composition of matter is a covalent conjugate of anantipsychotic agent and a fatty acid having 12-26 carbons. Preferablythe fatty acid in an unbranched common naturally occurring fatty acid.More preferably, the fatty acid has between 14 and 22 carbons.

Unbranched common naturally occurring fatty acids include C12:0 (lauricacid), C14:0 (myristic acid), C16:0 (palmitic acid), C16:1 (paalmitoleicacid), C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7(vaccenic), C18:2-6 (linoleic acid), C18:3-3 (α-linolenic acid), C18:3-5(eleostearic), C18:3-6 (β-linolenic acid), C18:4-3, C20:1 (gondoicacid), C20:2-6, C20:3-6 (dihomo-y-linolenic acid), C20:4-3, C20:4-6(arachidonic acid), C20:5-3 (eicosapentaenoic acid), C22:1 (docosenoicacid), C22:4-6 (docosatetraenoic acid), C22:5-6 (docosapentaenoic acid),C22:5-3 (docosapentaenoic), C22:6-3 (docosahexaenoic acid) and C24:1-9(nervonic). Highly preferred unbranched, naturally occurring fatty acidsare those with between 14 and 22 carbon atoms. The most preferred fattyacid is docosahexaenoic acid.

Antipsychotic agents include:Acetophenazine Maleate; AlentemolHydrobromide; Alpertine; Azaperone; Batelapine Maleate; Benperidol;Benzindopyrine Hydrochloride; Brofoxine; Bromperidol; BromperidolDecanoate; Butaclamol Hydrochloride; Butaperazine; Butaperazine Maleate;Carphenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine;Chlorpromazine Hydrochloride; Chlorprothixene; Cinperene; Cintriamide;Clomacran Phosphate; Clopenthixol; Clopimozide; Clopipazan Mesylate;Cloroperone Hydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride;Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; FluphenazineEnanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene;Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol;Haloperidol Decanoate; Iloperidone; Imidoline Hydrochloride; Lenperone;Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate; Metiapine;Milenperone; Milipertine; Molindone Hydrochloride; NaranolHydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine;Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide;Pinoxepin Hydrochloride; Pipamperone; Piperacetazine; PipotiazinePalmnitate; Piquindone Hydrochloride; Prochlorperazine Edisylate;Prochlorperazine Maleate; Promazine Hydrochloride; Quetiapine;Remoxipride; Quetiapine Remoxipride Hydrochloride; Risperidone;Risperadone Rimcazole Hydrochloride; Seperidol Hydrochloride;Sertindole; Setoperone; Spiperone; Thioridazine; ThioridazineHydrochloride; Thiothixene; Thiothixene Hydrochloride; TioperidoneHydrochloride; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride;Trifluperidol; Triflupromazine; Triflupromazine Hydrochloride; andZiprasidone Hydrochloride.

In certain preferred embodiments, involving compositions of matter, theconjugate of the fatty acid and the antipsychotic agent is selected fromthe foregoing agents, except that phenothiazines, butyrophenones andthioxanthenes are excluded.

The most preferred fatty acid is docosahexaenoic acid. The mostpreferred covalent conjugate is: ##STR1##

According to another aspect of the invention, a pharmaceuticalcomposition is provided. The pharmaceutical composition includes apharmaceutically acceptable carrier and a covalent conjugate of anantipsychotic agent and a fatty acid having 12-26 carbons. The covalentconjugate is present in the pharmaceutical composition in an amounteffective for treating a psychotic condition. The preferred fatty acids,bonds, antipsychotic agents and covalent conjugates are as describedabove.

The pharmaceutical composition also may comprise an antipsychotic agentother than the covalent conjugate. Suitable such antipsychotic agentsare selected from the group consisting of Acetophenazine Maleate;Alentemol Hydrobromide; Alpertine; Azaperone; Batelapine Maleate;Benperidol; Benzindopyrine Hydrochloride; Brofoxine; Bromperidol;Bromperidol Decanoate; Butaclamol Hydrochloride; Butaperazine;Butaperazine Maleate; Carphenazine Maleate; Carvotroline Hydrochloride;Chlorpromazine; Chlorpromazine Hydrochloride; Chlorprothixene;Cinperene; Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide;Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine;Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride;Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole; Flumezapine;Fluphenazine Decanoate; Fluphenazine Enanthate; FluphenazineHydrochloride; Fluspiperone; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Haloperidol; Haloperidol Decanoate;Iloperidone; Imidoline Hydrochloride; Lenperone; Mazapertine Succinate;Mesoridazine; Mesoridazine Besylate; Metiapine; Milenperone;Milipertine; Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepin Hydrochloride;Pipamperone; Piperacetazine; Pipotiazine Palmitate; PiquindoneHydrochloride; Prochlorperazine Edisylate; Prochlorperazine Maleate;Promazine Hydrochloride; Quetiapine; Remoxipride; RemoxiprideHydrochloride; Risperidone; Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Spiperone; Thioridazine;Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride;Tioperidone Hydrochloride; Tiospirone Hydrochloride; TrifluoperazineHydrochloride; Trifluperidol; Triflupromazine; TriflupromazineHydrochloride; and Ziprasidone Hydrochloride.

According to another aspect of the invention, a kit is provided. The kitcomprises a package which houses a container containing the covalentconjugate as described above. The package also houses instructions foradministering the covalent conjugate to a subject having a psychoticcondition.

According to another aspect of the invention, a second kit is provided.The kit comprises a package which houses a first container containingthe covalent conjugate described above and it further houses a secondcontainer containing an antipsychotic agent other than the covalentconjugate.

In the kits of the invention, the preferred fatty acids, bonds,antipsychotic agents and conjugates are as described above.

According to another aspect of the invention, a method is provided fortreating a psychotic condition. The method involves administering to asubject in need of such treatment a covalent conjugate of anantipsychotic agent and a fatty acid having 12-26 carbons, in an amounteffective to treat the psychotic condition. The preferred fatty acids,bonds, antipsychotic agents and conjugates are as described above.Likewise, cocktails as described above may be administered.

According to another aspect of the invention, a method is provided forachieving in a subject a therapeutic effect longer than the effectachieved if an equimolar amount of antipsychotic agents wereadministered. The method involves administering to a subject in need ofsuch treatment a covalent conjugate of the antipsychotic agent and afatty acid in an amount effective to achieve said therapeutic effect.The preferred fatty acids, bonds, antipsychotic agents and covalentconjugates are as described above.

According to still another aspect of the invention, a method is providedfor decreasing the number of daily doses required to achieve in asubject a therapeutic effect equivalent to that achieved if an equimolaramount of antipsychotic agent were administered to the subject. Themethod involves administering to a subject in need of such treatment acovalent conjugate of antipsychotic agents and a fatty acid in an amounteffective to achieve said therapeutic effect. Preferably, the covalentconjugate is administered not more than one time per day. The preferredfatty acids, bonds, antipsychotic agents and covalent conjugates are asdescribed above.

These and other aspects of the invention are described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which shows the dose response over time of clozapineagainst locomotor behavioral arousal induced by apomorphine. Clozapine1, 3, 10 refer to doses of clozapine at 1, 3 and 10 mg/kg, respectively,administered i.p.

FIG. 2 is a graph which shows the dose response over time ofDHA-clozapine against locomotor behavioral arousal induced byapomorphine. DHA-clozapine 1, 3, 10 refer to doses of DHA-clozapine at1, 3 and 10 mg/kg, respectively, administered i.p.

FIG. 3 is a graph which shows a comparison of the activity over time ofclozapine and DHA-clozapine against locomotor behavioral arousal inducedby apomorphine when administered at 3 mg/kg.

FIG. 4 is a graph which shows a comparison of the activity over time ofclozapine and DHA-clozapine against locomotor behavioral arousal inducedby apomorphine when administered at 10 mg/kg.

FIG. 5 is a graph which shows the molar-dose response of clozapine andDHA-clozapine at the 360-420 min time point for calculation of ED50.

DETAILED DESCRIPTION OF THE INVENTION

The invention involves the discovery that the extended therapeuticeffectiveness can be achieved if conjugates of antipsychotic agents andfatty acids are administered rather than unconjugated antipsychoticagents.

Clozapine is one of the class of "atypical" antipsychotics, having thefollowing structure: ##STR2## cis-docosahexaenoic acid (DHA) is anaturally occurring fatty acid. It is an unbranched chain fatty acidwith six double bonds, all cis. Its structure is as follows: ##STR3##

DHA can be isolated, for example, from fish oil or can be chemicallysynthesized. These methods, however, can generate trans isomers, whichare difficult and expensive to separate and which may present safetyproblems in humans. The preferred method of production is biologicalsynthesis to produce the all cis isomer. The preferred source of DHA isfrom Martek Biosciences Corporation of Columbia, Maryland. Martek has apatented system for manufacturing DHA using microalgae which synthesizeonly a single isomer of DHA, the all cis isomer. Martek's patentsinclude U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397,591.

DHA also is present in the milk of lactating women, and Martek'slicensee has obtained approval in Europe of DHA as a nutritionalsupplement for infant formula.

It is known that DHA can be unstable in the presence of oxygen. Tostabilize DHA and its conjugates it is important to add anti-oxidants tothe material after it is synthesized. One method of stabilization is tomake-up the newly synthesized material in the following solution: 100 gneat DHA-clozapine plus 100 g of vehicle (100 ml propylene glycol, 70 mgalpha-tocopherol, 5 mg dialaurylthiodipropionic acid, 50 mg ascorbicacid) prepared and held under argon in amber, sealed vials and stored atfour degrees centigrade. The following anti-oxidants may also beemployed: ascorbic acid, ascorbyl palmitate, dilauryl ascorbate,hydroquinone, butyated hydroxyanisole, sodium meta bisulfite, t-βcarotene and α-tocopherol. A heavy metal chelator such asethylenediamine tetra-acetic acid (EDTA) may also be used.

In one aspect of the invention, cocktails of the clozapine-fatty acidconjugate and another antipsychotic agent can be prepared foradministration to subjects having a need for such treatment. One ofordinary skill in the art is familiar with a variety of antipsychoticagents which are used in the medical arts to treat psychoses such asschizophrenia. Antipsychotic agents include Acetophenazine Maleate;Alentemol Hydrobromide; Alpertine; Azaperone; Batelapine Maleate;Benperidol; Benzindopyrine Hydrochloride; Brofoxine; Bromperidol;Bromperidol Decanoate; Butaclamol Hydrochloride; Butaperazine;Butaperazine Maleate; Carphenazine Maleate; Carvotroline Hydrochloride;Chlorpromazine; Chlorpromazine Hydrochloride; Chlorprothixene;Cinperene; Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide;Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine;Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride;Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole; Flumezapine;Fluphenazine Decanoate; Fluphenazine Enanthate; FluphenazineHydrochloride; Fluspiperone; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Haloperidol; Haloperidol Decanoate;Iloperidone; Imidoline Hydrochloride; Lenperone; Mazapertine Succinate;Mesoridazine; Mesoridazine Besylate; Metiapine; Milenperone;Milipertine; Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepin Hydrochloride;Pipamperone; Piperacetazine; Pipotiazine Palmitate; PiquindoneHydrochloride; Prochlorperazine Edisylate; Prochlorperazine Maleate;Promazine Hydrochloride; Quetiapine; Remoxipride; RemoxiprideHydrochloride; Risperidone; Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Spiperone; Thioridazine;Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride;Tioperidone Hydrochloride; Tiospirone Hydrochloride; TrifluoperazineHydrochloride; Trifluperidol; Triflupromazine; TriflupromazineHydrochloride; and Ziprasidone Hydrochloride.

The compounds of the invention, when used in alone or in cocktails, areadministered in therapeutically effective amounts. A therapeuticallyeffective amount will be determined by the parameters discussed below;but, in any event, is that amount which establishes a level of thedrug(s) effective for treating a psychotic disorder, includingschizophrenia.

When administered, the formulations of the invention are applied inpharmaceutically acceptable compositions. Such preparations mayroutinely contain salts, buffering agents, preservatives, compatiblecarriers, and optionally other therapeutic ingredients. When used inmedicine the salts should be pharmaceutically acceptable, butnon-pharmaceutically acceptable salts may conveniently be used toprepare pharmaceutically acceptable salts thereof and are not excludedfrom the scope of the invention. Such pharmacologically andpharmaceutically acceptable salts include, but are not limited to, thoseprepared from the following acids: hydrochloric, hydrobromic, sulphuric,nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic,tartaric, citric, methane sulfonic, formic, malonic, succinic,naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceuticallyacceptable salts can be prepared as alkaline metal or alkaline earthsalts, such as sodium, potassium or calcium salts.

Suitable buffering agents include: acetic acid and a salt (1-2% W/V);citric acid and a salt (1-3% W/V); and phosphoric acid and a salt(0.8-2% W/V).

Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V);chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal(0.004-0.02% W/V).

The active compounds of the present invention may be a pharmaceuticalcomposition having a therapeutically effective amount of a conjugate ofthe invention optionally included in a pharmaceutically-acceptablecarrier. The term "pharmaceutically-acceptable carrier" as used hereinmeans one or more compatible solid or liquid filler, dilutants orencapsulating substances which are suitable for administration to ahuman or other animal. The term "carrier" denotes an organic orinorganic ingredient, natural or synthetic, with which the activeingredient is combined to facilitate the application. The components ofthe pharmaceutical compositions are capable of being commingled with themolecules of the present invention, and with each other, in a mannersuch that there is no interaction which would substantially impair thedesired pharmaceutical efficacy.

Compositions suitable for parenteral administration convenientlycomprise a sterile preparation of the conjugates of the invention. Thispreparation may be formulated according to known methods.

The sterile preparation thus may be a sterile solution or suspension ina non-toxic parenterally-acceptable diluent or solvent. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or di-glycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables. Carrierformulations suitable for oral, subcutaneous, intravenous,intramuscular, etc. can be found in Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa.

The invention is used in connection with treating subjects having,suspected of having, developing or suspected of developing a psychoticcondition such as schizophrenia, or animals having or animals exhibitingsymptoms characteristic of schizophrenia.

The conjugates of the invention, when used in alone or in cocktails, areadministered in effective amounts. An effective amount means that amountalone or with multiple doses, necessary to delay the onset of, inhibitcompletely or lessen the progression of or halt altogether the onset orprogression of the psychotic condition such as schizophrenia. Ingeneral, an effective amount will be that amount necessary to inhibiteither negative or positive symptoms of the psychotic condition, andpreferably both negative and positive symptoms of the psychoticcondition such as schizophrenia. The inhibition of the negative and/orpositive symptoms of schizophrenia can be monitored by standardpsychiatric evaluation of the subject over time. In addition, otherphysiological methods for monitoring the changes in brain function whichaccompany symptoms of schizophrenia also can be employed to monitor theinhibition of the symptoms. For example, the state of advancement ofschizophrenia can be assessed using magnetic resonance imaging (MRI)(see, e.g., DeLisi et al., (Psychiatry Res. 74(3):129-140, 1997) orpositron emission tomography (PET) (see, e.g., Sabri et al., Lancet349:1735-1739, 1997; Andreasen et al., Lancet 349:1730-1734, 1997). Whenadministered to a subject, effective amounts will depend, of course, onthe particular condition being treated; the severity of the condition;individual patient parameters including age, physical condition, sizeand weight; concurrent treatment; frequency of treatment; and the modeof administration. These factors are well known to those of ordinaryskill in the art and can be addressed with no more than routineexperimentation. It is preferred generally that a maximum dose be used,that is, the highest safe dose according to sound medical judgment.

Dosage may be adjusted appropriately to achieve desired drug levels,locally or systemically. Generally, daily oral doses of active compoundswill be from about 0.01 mg/kg per day to 1000 mg/kg per day. It isexpected that IV doses in the same range will be effective. In the eventthat the response in a subject is insufficient at such doses, evenhigher doses (or effective higher doses by a different, more localizeddelivery route) may be employed to the extent that patient tolerancepermits. Continuous IV dosing over, for example 24 hours or multipledoses per day also are contemplated to achieve appropriate systemiclevels of compounds.

The preferred dose is believed to be at least 1/2, more preferably 1/4and even more preferably 1/6 or less than the dose required to achievethe same therapeutic effect when an equimolar amount of antipsychoticagent is administered but nonconjugated to a fatty acid. Clozapinetypically is administered in doses of 50-200 mg, 2-3 times per day.

A variety of administration routes are available. The particular modeselected will depend of course, upon the particular drug selected, theseverity of the disease state being treated and the dosage required fortherapeutic efficacy. The methods of this invention, generally speaking,may be practiced using any mode of administration that is medicallyacceptable, meaning any mode that produces effective levels of theactive compounds without causing clinically unacceptable adverseeffects. Such modes of administration include oral, rectal, sublingual,topical, nasal, transdermal or parenteral routes. The term "parenteral"includes subcutaneous, intravenous, intramuscular, or infusion. Oralroutes are preferred, although administration by injection may bepractical.

The compositions may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the conjugates of the inventioninto association with a carrier which constitutes one or more accessoryingredients. In general, the compositions are prepared by uniformly andintimately bringing the compounds into association with a liquidcarrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product.

Compositions suitable for oral administration may be presented asdiscrete units such as capsules, cachets, tablets, or lozenges, eachcontaining a predetermined amount of the active compound. Othercompositions include suspensions in aqueous liquors or non-aqueousliquids such as a syrup, an elixir, or an emulsion.

Other delivery systems can include time-release, delayed release orsustained release delivery systems. Such systems can avoid repeatedadministrations of the active compounds of the invention, increasingconvenience to the subject and the physician. Many types of releasedelivery systems are available and known to those of ordinary skill inthe art. They include polymer based systems such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; nonpolymersystems that are lipids including sterols such as cholesterol,cholesterol esters and fatty acids or neutral fats such as mono-, di andtriglycerides; hydrogel release systems; silastic systems; peptide basedsystems; wax coatings, compressed tablets using conventional binders andexcipients, partially fused implants and the like. In addition, apump-based hardware delivery system can be used, some of which areadapted for implantation.

A long-term sustained release implant also may be used. "Long-term"release, as used herein, means that the implant is constructed andarranged to deliver therapeutic levels of the active ingredient for atleast 30 days, and preferably 60 days. Long-term sustained releaseimplants are well known to those of ordinary skill in the art andinclude some of the release systems described above.

EXAMPLE

A) Synthesis of DHA-clozapine: ##STR4## Preparation of DHA-chloride:

To a solution of DHA (2.0 g, 6.08 mmol) in CH₂ Cl₂ (8 ml) was addedthionylchloride (2.22 ml, 30.4 mmol), at 0° C. under an Argon atmosphereand the reaction mixture was stirred at room temperature for 14 h.Excess thionylchloride was removed by co-evaporation with dry benzene (6ml) under reduced pressure. The resulting acid chloride was dried inhigh vacuum and subsequently used as such for the following reactionwithout purification. ##STR5## Preparation of Clozapine-DHA analog:

To a solution of clozapine (950 mg, 2.90 mmol) in dry toluene (30 ml)was added dry pyridine (235 μl, 2.90 mmol) followed by DHA-chloride(1.25 ml, 3.98 mmol) under an Argon atmosphere at room temperature. Thereaction mixture was refluxed for 3 h, cooled to room temperature, andstirred with 10% aq. Na₂ CO₃ solution (5 ml) for about 20 min. Thereaction mixture was washed with water (3×20 ml), the combined aqueousphase was extracted once with ether (20 ml), the organic phase was dried(Na₂ SO₄) and concentrated under reduced pressure. The residue waspurified by chromatography on florisil with 98:2 CHCl₃ -methanol aseluent to yield the clozapine-DHA analog as an orange red viscous liquid(1.65 g, 89%).

NMR analysis of the product was as follows:

¹ H NMR (300 MMz, CDCl₃): δ0.97 (t, J=7.6 Hz, 3 H), 2.07 (apparentquintet, J=7.4 Hz, 2 H), 2.15-2.29 (m, 8 H), 2.29 (s, 3 H), 2.73-2.68(m, 10 H), 3.48-3.90 (m, 4 H), 5.25-5.44 (m, 12 H), 6.96 (dd, J=8.4, 2.4Hz, 1 H), 7.12 (d, J=8.4 Hz, 1 H), 7.36-7.50 (m, 3 H), 7.25-7.55 (m, 1H).

³ C NMR (75 MHz, CDCl₃): δ14.22, 20.50 (2C), 22.82, 25.48, 25.49 (2C),25.578 (4C),33.44, 45.91, 54.66, 123.19, 126.10, 126.65, 126.97, 127.63,127.81, 127.83 (2C), 128.07, 128.09, 128.15 (2C), 128.21 (2C), 128.51(2C), 129.07 (2C), 131.97, 132.01, 133.37, 133.94, 144.72, 146.13,160.29 and 172.98.

B) Methods of Use:

Experimental Procedures

Animals:rats.

Rats/group: nine.

Route of administration: i.p.

Clozapine and DHA-clozapine were made-up to a 50% w/w solution inpropylene glycol. This solution was injected directly into theperitoneum at the appropriate dose.

Physiological Measurements:

A standard animal model of schizophrenia symptoms (apomorphine increasedhyper-locomotion) was used to assess the activity of the DHA-clozapineconjugate. To start the experiment, 1.0 mg/kg of R(-)apomorphine wasinjected into the peritoneum of each rat, which caused the locomotoractivity of the rats to increase. The DHA-clozapine conjugate was thenadministered i.p., and the drug's effect on apomorphine increasedhyper-locomotion was measured electronically in a computerized activitymonitoring system.

Results:

DHA-clozapine and clozapine were both active against locomotorbehavioral arousal induced by 1 mg/kg, i.p., of R(-) apomorphine, withinan hour after injection of the tested central depressants at doses of 10mg/kg, i.p. (FIGS. 1 & 2).

DHA-clozapine was much longer acting than clozapine, in that the effectof doses of DHA-clozapine of 3 mg/kg, i.p., persisted for 24 hours afteradministration. In contrast, the effect of clozapine persisted weaklyfor not more than 2 or 4 hours at that dose. At 10 mg/kg, DHA-clozapineproduced profound inhibition of behavioral arousal that persisted forlonger than 25 hours, whereas behavior had returned to control levelswithin 3-5 hours after administration of clozapine. Thus, DHA-clozapinewas at least six-times longer-acting, and probably even morelonger-acting if equimolar doses were compared. (FIGS. 2 & 3, in whichasterisks indicate p<0.05 for planned post-hoc comparisons by Scheffe'stest after a two-way ANOVA for effect of drug and testing time: F 1,80df!=80.3 at 3 mg/kg, and F 1,80 df! 146 at 10 mg/kg; both p<0.0001 for adifference between drugs).

On a molar-dose basis (MW of clozapine=327; DHA-clozapine=637), withtesting at hours 3-4 after dosing, DHA-CLZ produced 50% inhibition oflocomotor arousal induced by R(-)-apomorphine at about 3.5 μmol/kg,i.p., whereas clozapine itself required a dose of about 22.5 μmol/kg toproduce the same effect (FIG. 4). Thus, the DHA-derivative wasapproximately 6.4-times more potent.

In conclusion, DHA-clozapine appears to be a potent, long-acting centraldepressant with powerful and prolonged antiapomorphine activity in therat after systemic injection, with the ED50 of about 3.5 μmol/kg, i.p.,and duration of action of more than 24 hours after doses on the order of10-15 μmol/kg.

Such an increase in half-life has a number of medical implications suchas better control of patients' psychotic symptoms since the longerhalf-life should allow "once a day dosing" and at lower doses. Lowertotal doses should result in a decrease of the peripherally and perhapscentrally mediated side-effects of clozapine.

Other aspects of the invention will be clear to the skilled artisan andneed not be repeated here. All patents, published patent applicationsand literature cited herein are incorporated by reference in theirentirety.

While the invention has been described with respect to certainembodiments, it should be appreciated that many modifications andchanges may be made by those of ordinary skill in the art withoutdeparting from the spirit of the invention. It is intended that suchmodification, changes and equivalents fall within the scope of thefollowing claims.

We claim:
 1. A composition of matter comprisinga covalent conjugate ofan antipsychotic agent and a fatty acid having 12-26 carbons except thatthe antipsychotic agent is not a phenothiazine, butyrophenone orthioxanthene, and wherein the antipsychotic agent is selected from thegroup consisting of: Alentemol Hydrobromide; Alpertine; BatelapineMaleate; Benzindopyrine Hydrochloride; Brofoxine; Bromperidol;Bromperidol Decanoate; Butaclamol Hydrochloride; Butaperazine;Butaperazine Maleate; Carphenazine Maleate; Carvotroline Hydrochloride;Cinperene; Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide;Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine;Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride; EtazolateHydrochloride; Fenimide; Flucindole; Flumezapine; Fluspirilene;Flutroline; Gevotroline Hydrochloride; Halopemide; Iloperidone;Imidoline Hydrochloride; Lenperone; Mazapertine Succinate; Metiapine;Milenperone; Milipertine; Molindone Hydrochloride; NaranolHydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine;Oxiperomide; Penfluridol; Pentiapine Maleate; Pimozide; PinoxepinHydrochloride; Pipamperone; Piperacetazine; Pipotiazine Palmitate;Piquindone Hydrochloride; Ouetiapine; Remoxipride; QuetiapineRemoxipride Hydrochloride; Risperidone; Risperadone RimcazoleHydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone;Tioperidone Hydrochloride; Tiospirone Hydrochloride; and ZiprasidoneHydrochloride.
 2. The composition of matter of claim 1, wherein thefatty acid is an unbranched, naturally occurring fatty acid.
 3. Thecomposition of matter of claim 2, wherein the fatty acid has 14≧22carbons.
 4. The composition of matter of claim 2, wherein the fatty acidis docosahexaenoic acid.
 5. A pharmaceutical composition comprisingacovalent conjugate of an antipsychotic agent and a fatty acid having12-26 carbons in an amount effective for treating a psychotic condition,and a pharmaceutically acceptable carrier except that the antipsychoticagent is not a phenothiazine, butyrophenone or thioxanthene, and whereinthe antipsychotic agent is selected from the group consisting of:Alentemol Hydrobromide; Alpertine; Batelapine Maleate; BenzindopyrineHydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate; ButaclamolHydrochloride; Butaperazine; Butaperazine Maleate; Carphenazine Maleate;Carvotroline Hydrochloride; Cinperene; Cintriamide; Clomacran Phosphate;Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Etazolate Hvdrochloride; Fenimide;Flucindole; Flumezapine; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Iloperidone; Imidoline Hydrochloride;Lenperone; Mazapertine Succinate; Metiapine; Milenperone; Milipertine;Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Pimozide; Pinoxepin Hydrochloride; Pipamperone;Piperacetazine; Pipotiazine Palmitate; Piquindone Hydrochloride;Quetiapine; Remoxipride; Quetiapine Remoxipride Hydrochloride;Risperidone; Risperadone Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Tioperidone Hydrochloride;Tiospirone Hydrochloride; and Ziprasidone Hydrochloride.
 6. Thepharmaceutical composition of claim 5, wherein the fatty acid is anunbranched, naturally occurring fatty acid.
 7. The pharmaceuticalcomposition of claim 6, wherein the fatty acid has 14-22 carbons.
 8. Thepharmaceutical composition of claim 6, wherein the fatty acid isdocosahexaenoic acid.
 9. The pharmaceutical composition of any of claims5-8 further comprising an antipsychotic agent other than the covalentconjugate.
 10. The pharmaceutical composition of claim 9, wherein theantipsychotic agent other than the covalent conjugate is selected fromthe group consisting of Acetophenazine Maleate; Alentemol Hydrobromide;Alpertine; Azaperone; Batelapine Maleate; Benperidol; BenzindopyrineHydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate; ButaclamolHydrochloride; Butaperazine; Butaperazine Maleate; Carphenazine Maleate;Carvotroline Hydrochloride; Chlorpromazine; ChlorpromazineHydrochloride; Chlorprothixene; Cinperene; Cintriamide; ClomacranPhosphate; Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride;Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; FluphenazineEnanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene;Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol;Haloperidol Decanoate; Iloperidone; Imidoline Hydrochloride; Lenperone;Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate; Metiapine;Milenperone; Milipertine; Molindone Hydrochloride; NaranolHydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine;Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide;Pinoxepin Hydrochloride; Pipamperone; Piperacetazine; PipotiazinePalmitate; Piquindone Hydrochloride; Prochlorperazine Edisylate;Prochlorperazine Maleate; Promazine Hydrochloride; Quetiapine;Remoxipride; Remoxipride Hydrochloride; Risperidone; RimcazoleHydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone;Spiperone; Thioridazine; Thioridazine Hydrochloride; Thiothixene;Thiothixene Hydrochloride; Tioperidone Hydrochloride; TiospironeHydrochloride; Trifluoperazine Hydrochloride; Trifluperidol;Triflupromazine; Triflupromazine Hydrochloride; and ZiprasidoneHydrochloride.
 11. A kit comprising a package housinga containercontaining the covalent conjugate of any of claims 1-4, and also housinginstructions for admninistering to a subject having a psychoticcondition the covalent conjugate.
 12. A kit comprising a packagehousinga first container containing the covalent conjugate of any ofclaims 1-4, and a second container containing an antipsychotic agentother that the covalent conjugate.
 13. A method for treating a psychoticcondition comprisingadministering to a subject in need of such treatmentof a covalent conjugate of an antipsychotic agent and a fatty acidhaving 12-26 carbons, in an amount effective to treat the psychoticcondition, except that the antipychotic agent is not a phenothiazine,butyrophenone or thioxanthene, and wherein the antipsychotic agent isselected from the group consisting of Alentemol Hydrobromide; Alpertine;Batelapine Maleate; Benzindopyrine Hidrochloride; Brofoxine;Bromperidol; Bromperidol Decanoate; Butaclamol Hydrochloride;Butaperazine; Butaperazine Maleate; Carphenazine Maleate; CarvotrolineHydrochloride; Cinperene; Cintriamide; Clomacran Phosphate;Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Etazolate Hydrochloride; Fenimide;Flucindole; Flumezapine; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Iloperidone; Imidoline Hydrochloride;Lenperone; Mazapertine Succinate; Metiapine; Milenperone; Milipertine;Molindone Hydrochloride; Naranol Hydrochloride, NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Pimozide; Pinoxepin Hydrochloride; Pipamperone;Piperacetazine; Pipotiazine Palmitate; Piguindone Hydrochloride;Quetiapine; Remoxipride; Quetiapine Remoxipride Hydrochloride;Risperidone; Risperadone Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Tioperidone Hydrochloride;Tiospirone Hydrochloride; and Ziprasidone Hydrochloride.
 14. The methodof claim 13, wherein the fatty acid is an unbranched, naturallyoccurring fatty acid.
 15. The method of claim 14, wherein the fatty acidhas 14-22 carbons.
 16. The method of claim 14, wherein the fatty acid isdocosahexaenoic acid.
 17. The method of any of claims 13-16 furthercomprising an antipsychotic agent other than the covalent conjugate. 18.The method of claim 17, wherein the antipsychotic agent other than thecovalent conjugate is selected from the group consisting ofAcetophenazine Maleate; Alentemol Hydrobrornide; Alpertine; Azaperone;Batelapine Maleate; Benperidol; Benzindopyrine Hydrochloride; Brofoxine;Bromperidol; Bromperidol Decanoate; Butaclamol Hydrochloride;Butaperazine; Butaperazine Maleate; Carphenazine Maleate; CarvotrolineHydrochloride; Chlorpromazine; Chlorpromazine Hydrochloride;Chlorprothixene; Cinperene; Cintriamide; Clomacran Phosphate;Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride;Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; FluphenazineEnanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene;Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol;Haloperidol Decanoate; Iloperidone; Imidoline Hydrochloride; Lenperone;Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate; Metiapine;Milenperone; Milipertine; Molindone Hydrochloride; NaranolHydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine;Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide;Pinoxepin Hydrochloride; Pipamperone; Piperacetazine; PipotiazinePalmitate; Piquindone Hydrochloride; Prochlorperazine Edisylate;Prochlorperazine Maleate; Promazine Hydrochloride; Quetiapine;Remoxipride; Remoxipride Hydrochloride; Risperidone; RimcazoleHydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone;Spiperone; Thioridazine; Thioridazine Hydrochloride; Thiothixene;Thiothixene Hydrochloride; Tioperidone Hydrochloride; TiospironeHydrochloride; Trifluoperazine Hydrochloride; Trifluperidol;Triflupromazine; Triflupromazine Hydrochloride; and ZiprasidoneHydrochloride.
 19. The method of claim 13-16 wherein the psychoticcondition is schizophrenia.
 20. A method for achieving in a subject atherapeutic effect longer than that achieved when an equimolar amount ofan antipsychotic agent is administered, comprisingadministering to asubject in need of such treatment a covalent conjugate of theantipsychotic agent and a fatty acid in an amount effective to achievesaid therapeutic effect, except that the antipsychotic agent is not aphenothiazine, butyrophenone or thioxanthene, and wherein theantipsychotic agent is selected from the group consisting of: AlentemolHydrobromide; Alpertine; Batelapine Maleate; BenzindopyrineHydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate; ButaclamolHydrochloride; Butaperazine; Butaperazine Maleate; Carphenazine Maleate;Carvotroline Hydrochloride; Cinperene; Cintriamide; Clomacran Phosphate;Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Etazolate Hydrochloride; Fenimide;Flucindole; Flumezapine; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Iloperidone; Imidoline Hydrochloride;Lenperone; Mazapertine Succinate; Metiapine; Milenperone; Milipertine;Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Pimozide; Pinoxepin Hydrochloride; Pipamperone;Piperacetazine; Pipotiazine Palmitate; Piquindone Hydrochloride;Quetiapine; Remoxipride; Quetiapine Remoxipride Hydrochloride;Risperidone; Risperadone Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Tioperidone Hydrochloride;Tiospirone Hydrochloride; and Ziprasidone Hydrochloride.
 21. The methodof claim 20, wherein the fatty acid is an unbranched, naturallyoccurring fatty acid.
 22. The method of claim 21, wherein the fatty acidhas 14-22 carbons.
 23. The method of claim 21, wherein the fatty acid isdocosahexaenoic acid.
 24. A method for decreasing the number of dailydoses required to achieve in a subject a therapeutic effect equivalentto that achieved when an equimolar amount of antipsychotic agent isadministered comprisingadministering to a subject in need of suchtreatment a covalent conjugate of the antipsychotic agent and a fattyacid in an amount effective to achieve said therapeutic effect, andwherein the antipsychotic agent is selected from the group consistingof: Alentemol Hydrobromide; Alpertine; Batelapine Maleate;Benzindopyrine Hydrochloride, Brofoxine; Bromperidol; BromperidolDecanoate; Butaclamol Hydrochloride; Butaperazine; Butaperazine Maleate;Carphenazine Maleate; Carvotroline Hydrochloride; Cinperene;Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide; ClopipazanMesylate; Cloroperone Hydrochloride; Clothiapine; Clothixamide Maleate;Clozapine; Cyclophenazine Hydrochloride; Etazolate Hydrochloride;Fenimide; Flucindole; Flumezapine; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Iloperidone; Imidoline Hydrochloride;Lenperone; Mazapertine Succinate; Metiapine; Milenperone; Milipertine;Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Pimozide; Pinoxepin Hydrochloride; Pipamperone;Piperacetazine; Pipotiazine Palmitate; Piguindone Hydrochloride;Quetiapine; Remoxipride; Quetiapine Remoxipride Hydrochloride;Risperidone; Risperadone Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Tioperidone Hydrochloride;Tiospirone Hydrochloride; and Ziprasidone Hydrochloride.
 25. The methodof claim 24, wherein the fatty acid is an unbranched, naturallyoccurring fatty acid.
 26. The method of claim 25, wherein the fatty acidhas 14-22 carbons.
 27. The method of claim 25, wherein the fatty acid isdocosahexaenoic acid.
 28. The method of claim 24-27, wherein thecovalent conjugate is administered not more than once per day.
 29. Amethod for reducing the amount of antipsychotic agent administered to asubject having a psychotic condition treatable by said antipsychoticagent, comprisingadministering a covalent conjugate of saidantipsychotic agent and a fatty acid having 12-26 carbons to saidsubject at a molar dose at least 50% below the dose of the unconjugatedantipsychotic agent necessary to achieve the same therapeutic effect asis achieved with said conjugate, and wherein the antipsychotic agent isselected from the group consisting of: Alentemol Hydrobromide;Alpertine; Batelapine Maleate; Benzindopyrine Hydrochloride; Brofoxine;Bromperidol; Bromperidol Decanoate; Butaclamol Hydrochloride;Butaperazine; Butaperazine Maleate; Carphenazine Maleate; CarvotrolineHydrochloride; Cinperene; Cintriamide; Clomacran Phosphate;Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Etazolate Hydrochloride; Fenimide;Flucindole; Flumezapine; Fluspirilene; Flutroline; GevotrolineHydrochloride; Halopemide; Iloperidone; Imidoline Hydrochloride;Lenperone; Mazapertine Succinate; Metiapine; Milenperone; Milipertine;Molindone Hydrochloride; Naranol Hydrochloride; NeflumozideHydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;Pentiapine Maleate; Pimozide; Pinoxepin Hydrochloride; Pipamperone;Piperacetazine; Pipotiazine Palmitate; Piquindone Hydrochloride;Quetiapine; Remoxipride; Quetiapine Remoxipride Hydrochloride;Risperidone; Risperadone Rimcazole Hydrochloride; SeperidolHydrochloride; Sertindole; Setoperone; Tioperidone Hydrochloride;Tiospirone Hydrochloride; and Ziprasidone Hydrochloride.
 30. The methodof claim 29, wherein the fatty acid is an unbranched, naturallyoccurring fatty acid.
 31. The method of claim 30, wherein the fatty acidhas 14-22 carbons.
 32. The method of claim 30, wherein the fatty acid isdocosahexaenoic acid.